This is an ongoing long-range study of the actions of purine antimetabolites on tumors and normal tissues. The studies involve several interrelated areas: 1) Adenosine deaminase (ADA) and its inhibition. The tight-binding inhibitor, deoxycoformycin (dCF) is under study in intact cells and whole animals. Evidence has been present indicating that the nucleoside transport system plays a rate-limiting role in the inactivation of intracellular ADA by dCF. Temperature dependence studies will be undertaken with both the on and off reactions with isolated enzyme and for further evaluation of the transport system. 2) 5'-methylthioadenosine phosphorylase (MTA-Pase), a target enzyme for drug development through studies with various 5'-methylthioadenosine (MTA) analogs, three types of potential agents have been identified: a) those that liberate a toxic adenine analog which is converted to analog nucleotides by APRT, b) those that liberate a toxic sugar-phosphate, e.g., 5-ribose-1-phosphate from 5'-iodoadenosine, c) competitive inhibitors of the enzyme, e.g., 5'-iodoformycin, 5'-chloroformycin; these analogs have Ki values of 1-5 times 10 to the minus 7th power M. Recent evidence indicates that certain of these compounds block mitogenesis in lymphocytes and produce promising inhibition in various tumor cells. 3) Analog nucleosides and blood platelet aggregation. Recently we have learned that the adenosine analogs, 2', 5'-dideoxyadenosine (ADA) and MTA, both block the inhibitory effects of adenosine on ADP-induced platelet aggregation. DDA overcomes the effects of prostaglandin, PGE1, whereas MTA does not. DDA inhibits platelet adenylate cyclase whereas MTA does not. Thus these analogs operate by different mechanisms. Since MTA is a naturally produced nucleoside, the possibility exists that it may play a role in the regulation of platelet behavior.